The present invention provides novel antifungal glycopeptides compounds for preventing or treating fungal infection and at least one novel amino acid residue related thereto. The present invention in a preferred embodiment also provides a pharmaceutical and agricultural composition that comprises the novel compounds and salts thereof for treating or preventing fungal infection. The invention in a further embodiment provides for the new bacterial strain that produces the new antifungal compounds.
There is a growing demand for new antifungals, given the increasing prevalence of pathogens resistant to current antifungal agents. Four major therapeutic groups of antifungal agents currently exist: polyene antifungals, azole antifungals, allylamine antifungals, and the cchinocandins. The first three groups primarily target ergosterol production or bind to ergosterol. disrupting the fungal membrane. Ergosterol, much like cholesterol found in mammalian cells, is important for maintaining proper cell permeability and fluidity. The echinocandins, the fourth group, are synthetically-modified lipopeptides that originate from the natural compound echinocandin B produced by Aspergillus nidulans. In fungi, two covalently cross-linked polysaccharides, (1,3)-β-glucan and chitin, form the primary scaffold that is responsible for the structural integrity and shape of the cell wall. The cchinocandin class of antifungal agents inhibit (1,3)-β-glucan synthase, an enzyme complex that polymerizes uridine diphosphate glucose into (1,3)-β-glucan polymers.
A striking feature of some strains of Burkholderia is production of various antifungal compounds, which make the organism potentially useful for management of fungal diseases. However, isolation of Burkholderia spp. from cystic fibrosis patients reclassified them as opportunistic pathogens, consequently preventing the direct use of the bacteria for fungal disease management. Isolation and identification of antifungals responsible for the observed plant-disease suppression activities of the Burkholderia strains will provide important avenues for the development of biological-based fungicides, while eliminating potential health risks from using the bacteria directly. Novel antifungals are needed because of the importance of fungal infections in immunocompromised patients, and the limitations of currently-available antifungal agents regarding their spectra of activity and toxicities. In addition, new antifungals arc crucial for food preservation and production of a sufficient and affordable food supply. In this disclosure, we characterize the structure and activity of a new antifungal compound named occidiofungin, meaning fungal killer. The complete covalent structure of the anti fungal has been elucidated by TOCSY, NOESY, ROESY, and HSQC 2D NMR spectroscopy experiments. Occidiofungin's antifungal activity against a variety of animal and fungal pathogens has been tested and proven. Additionally, aberrant membrane morphology, similar to what has been reported for the cchinocandins class of antifungals, was observed following exposure to sub-lethal concentrations of occidiofungin, suggesting that occidiofungin also targets the cell envelope. This work provides a substantial base for future experiments aimed at understanding the compound's mode of action, as well as investigating occidiofungin's pharmaceutical and agricultural potential.
As a result, a need exists in the field of fungicides for new antifungal compounds effective against animal and plant pathogens that are resistant to typical fungicidal agents. The present invention provides such a compound and composition.